Current pharmacotherapy options for conduct disorders in adolescents and children.

INTRODUCTION: Conduct disorder (CD) is a common mental health disorder of childhood and adolescence. CD's complexity, with its heterogenous clinical manifestations and overlapping comorbidities makes the application of evidence-based management approaches challenging. This article aims to combine a systematic review of the available literature, with a consensus opinion from both child and adolescent psychiatrists and developmental pediatricians on the clinical and pharmacological management of children and adolescents with conduct disorder (CD). AREAS COVERED: The authors review the CD population and provide a systematic review and meta-analysis of the effectiveness and safety of pharmacotherapies using preferred reporting items for systematic review and meta-analysis (PRISMA) and strength of evidence recommendation taxonomy (SORT) guidelines. The authors then provide an expert clinical opinion for the use of different pharmacotherapies to address aggressive and disruptive behavior in children. EXPERT OPINION: Atypical antipsychotics (e.g. risperidone) demonstrate evidence for efficacy in CD. Other pharmacotherapies (e.g. mood stabilizers, anticonvulsants, psychostimulants and selective norepinephrine reuptake inhibitors) have a low level of evidence for CD alone, however, can sometimes be effective in managing the symptoms of CD when other psychiatric disorders are also present.

Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor.

Pain therapeutics discovered by molecular mining of the expressed genome of Australian predatory cone snails are providing lead compounds for the treatment of neurological diseases such as multiple sclerosis, shingles, diabetic neuropathy and other painful neurological conditions. The high specificity exhibited by these novel compounds for neuronal receptors and ion channels in the brain and nervous system indicates the high degree of selectivity that this class of neuropeptides can be expected to show when used therapeutically in humans. A lead compound, ACV1 (conotoxin Vc1.1 from Conus victoriae), has entered Phase II clinical trials and is being developed for the treatment for neuropathic pain. ACV1 will be targeted initially for the treatment of sciatica, shingles and diabetic neuropathy. The compound is a 16 amino acid peptide [Sandall et al., 2003. A novel alpha-conotoxin identified by gene sequencing is active in suppressing the vascular response to selective stimulation of sensory nerves in vivo. Biochemistry 42, 6904-6911], an antagonist of neuronal nicotinic acetylcholine receptors. It has potent analgesic activity following subcutaneous or intramuscular administration in several preclinical animal models of human neuropathic pain [Satkunanathan et al., 2005. Alpha conotoxin Vc1.1 alleviates neuropathic pain and accelerates functional recovery of injured neurons. Brain. Res. 1059, 149-158]. ACV1 may act as an analgesic by decreasing ectopic excitation in sensory nerves. In addition ACV1 appears to accelerate the recovery of injured nerves and tissues.

Alpha-conotoxin Vc1.1 alleviates neuropathic pain and accelerates functional recovery of injured neurones.

This paper demonstrates the capacity of the neuronal nicotinic acetylcholine receptor (nAChR) antagonist alpha-conotoxin Vc1.1 to inhibit pain responses in vivo. Vc1.1 suppressed pain behaviors when tested in two models of peripheral neuropathy of the rat sciatic nerve, the chronic constriction injury (CCI) and partial nerve ligation (PNL) models. Mechanical hyperalgesia was assessed using an Ugo Basile Analgesymeter. Vc1.1 was administered by intramuscular bolus injection near the site of injury at doses of 0.036 microg, 0.36 microg and 3.6 microg in CCI rats and at a dose of 0.36 microg in PNL rats. Vc1.1 was also administered contralaterally in CCI rats at doses of 0.36 microg and 3.6 microg. Treatment started after the development of hyperalgesia and continued for 7 days. Vc1.1 significantly attenuated mechanical hyperalgesia in both CCI and PNL rats for up to a week following cessation of treatment. Vc1.1 also accelerated functional recovery of injured neurones. A blister was raised over the footpad innervated by the peripheral terminals of the injured nerve. The ability of these terminals to mount an inflammatory vascular response upon perfusion of the blister base with substance P provided a measure of functional recovery. This study shows that alpha-conotoxin Vc1.1, a neuronal nAChR antagonist, suppressed mechanical pain responses associated with peripheral neuropathy in rats in vivo and accelerated functional recovery of the injured neurones. A role for neuronal nAChRs in the analgesic activity of Vc1.1 is proposed.

Optimizing the connectivity in disulfide-rich peptides: alpha-conotoxin SII as a case study.

We describe a strategy for the efficient, unambiguous assignment of disulfide connectivities in alpha-conotoxin SII, of which approximately 30% of its mass is cysteine, as an example of a generalizable technique for investigation of cysteine-rich peptides. alpha-Conotoxin SII was shown to possess 3-8, 2-18, and 4-14 disulfide bond connectivity. Sequential disulfide bond connectivity analysis was performed by partial reduction with Tris(2-carboxyethyl)phosphine and real-time mass monitoring by direct-infusion electrospray mass spectrometry (ESMS). This method achieved high yields of the differentially reduced disulfide bonded intermediates and economic use of reduced peptide. Intermediates were alkylated with either N-phenylmaleimide or 4-vinylpyridine. The resulting alkyl products were assigned by ESMS and their alkyl positions sequentially identified via conventional Edman degradation. The methodology described allows a more efficient, rapid, and reliable assignment of disulfide bond connectivity in synthetic and native cysteine-rich peptides.